Attikon University Hospital, Management of Iron Deficiency in Heart Failure : Current Evidence and Practical Recommendations for the use of Ferric Carboxymaltose J. Parissis Heart Failure Unit, Attikon University Hospital, Athens, Greece

Disclosures Grants: ALARM investigator received research grants by Abbott US and Orion Pharma Horonaria: received horonaria for advisory boards and lectures from Novartis, Pfizer, Menarini, Servier , Roche diagnostics and Genesis Pharma Journals: Associate Editor of EJHF ESC HF GLs: Member of task force

Case summary History: 67 year-old female 3-year history of HF due to drug-induced dilated cardiomyopathy (LVEF: 30%) (history of breast cancer on doxorubicin) Presentation: NYHA II Body weight 73 Kgs NT-proBNP: 1015 pg/ml SBP 110/60mm Hg HR 66/min QRS duration: 115 ms 6 min Walking Distance: 360 meters GFR: 62 ml/min HB: 10,9 mg/dl

Chronic management Oral medications Sacubitril/Valsartan 200 mg bid Bisoprolol 7,5 mg Furosemide 80 mg Eplerenone 50 mg ICD Management of co-morbidities Evaluation for transplantation/LVAD implantation

Pt was Investigated for iron deficiency Diagnostic work-up for anemia History, lab test negative for malignancy Iron deficiency (Ferritin=28 μg/L – TSAT=12%) Folic acid, B12: normal Gastrointestinal endoscopy: negative

Iron deficiency management Fe deficit(mg)= = 1080mg iv Fe administration Ferric carvoxymaltose 1000mg (for 15 min). New administration of 500 mg after 6 weeks (ferritin: 88 μg/L) Evaluation after 12, 24 weeks since therapy completion

8 weeks later NYHA: I-II 6MWT: 400 meters Laboratory tests: Hb=12,1 mg/dL Urea=60 mg/dL, Creatinine=1,3 mg/dL Sodium=140 mEq/L, Potassium=4,1 mEq/L BNP=501 pg/ml Ferritin: 102 μg/dl

Etiology & pathophysiology of anemia in HF Anemia of Chronic Disease Pharmaco- therapy Renal Dysfunction Malnutrition Decreased Cardiac Output Inflammation Bone marrow dysfunction Abnormal iron homeostasis (uptake, release, utilization) Intravascular fluid imbalance (hemodilution) EPO deficiency or resistance

Etiology of anemia in advanced CHF 37 pts, advanced CHF, LVEF 25% Iron deficiency: absence of iron stores in bone marrow Hemodilution: Normal RBC volume by Cr-51 labeled RBC Drug-induced: enalapril (restoration after discont.) Chronic disease anemia: no specific cause found Nanas et al, J Am Coll Cardiol 2006

Functional iron deficiency and diastolic function in heart failure with preserved ejection fraction

Depleted iron stores are associated with inspiratory muscle weakness independently of skeletal muscle mass in men with systolic chronic heart failure

Role of iron deficiency in the pathogenesis of exercise intolerance van Veldhuisen, D. J. et al. (2011) Anemia and iron deficiency in heart failure: mechanisms and therapeutic approaches Nat. Rev. Cardiol. doi:10.1038/nrcardio.2011.77

Clinical trials in iron repletion van Veldhuisen et al, Nature Rev Cardiol 2011

What is Ferric Carboxymaltose? Ribbon-like carboxymaltose Ferric hydroxide molecules Stable polynuclear iron complex Essentially no release of ionic iron in circulation Dextran-free carbohydrate shell (low immunogenic potential) No test dose Physiological pH and osmolarity Rapid administration of up to 1000 mg iron Macdougall & Ashenden, Adv Chron Kid Dis 2009 26

FAIR-HF study design Anker SD, Colet C, Filippatos G, et al FAIR-HF study design Anker SD, Colet C, Filippatos G, et al. Eur J Heart Fail 2009;11:1084–91. Main inclusion criteria: NYHA class II/III, LVEF ≤40% (NYHA II) or ≤45% (NYHA III) Hb: 9.5–13.5 g/dL Iron deficiency: serum ferritin <100 µg/L or <300 µg/L, if TSAT <20% Treatment adjustment algorithm: Interruption: Hb >16 g/dL or serum ferritin >800 µg/L or serum ferritin >500 µg/L, if TSAT >50% Restart: Hb <16 g/dL and serum ferritin <400 µg/L and TSAT<45% Blinding: Clinical staff: unblinded and blinded personnel Patients: usage of curtains and black syringes for injections * Total dose required for repletion calculated using the Ganzoni formula FAIR-HF=Ferric carboxymaltose Assessment in patients with IRon deficiency and chronic Heart Failure; Hb=haemoglobin; i.v.=intravenous; LVEF=left ventricular ejection volume; NYHA=New York Heart Association; PGA=patient global assessment; TSAT=transferrin saturation

Primary and secondary endpoints in FAIR-HF Self-reported Patient Global Assessment score at week 24 NYHA class at week 24 (adjusted for baseline NYHA class) Key secondary PGA score and NYHA class* at Weeks 4 and 12 Six-minute walk test distance** KCCQ score** EQ-5D questionnaire score** Safety endpoints * adjusted for baseline **at weeks 4, 12 and 24 and adjusted for baseline EQ-5D=European Quality of Life-5; KCCQ=Kansas City Cardiomyopathy Questionnaire Anker SD, et al. Eur J Heart Fail 2009;11:1084–91.

Intravenous iron in CHF FAIR-HF: Primary endpoints Patient Global Assessment at Week 24 OR for better rank: 2.51 p<0.001 NYHA Functional Class at Week 24 OR for improvement by 1 class: 2.40 p<0.001 459 pts, NYHA II-III, LVEF<45%, with iron deficiency (ferritin <100 ng/mL or 100-299 if TSAT <20%) Ferric carboxymaltose iv 200mg/week to iron repletion, then 200mg/month vs placebo Anker et al. N Engl J Med 2009

Intravenous iron in CHF FAIR-HF: secondary endpoints 6-minute walk test KCCQ overall score EQ-5D VAS score p<0.001 Anker et al. N Engl J Med 2009

Patient Global Assessment FAIR-HF results: intravenous iron performed better than placebo in all patient subgroups Patient Global Assessment NYHA functional class Haemoglobin (g/dL) ≤12 >12 Median serum ferritin (μg/L) ≤39 >39 eGFR (mL/min/1.73 m2) ≤60 >60 Median age (years) ≤69.7 ≥69.7 Gender Male Female NYHA Class II Class III Median ejection fraction (%) ≤33 >33 CHF Non-ischaemic Ischaemic Diabetes No Yes Median BMI (kg/m2) ≤27.37 >27.37 Anker SD, et al. N Engl J Med 2009;361:2436–48. BMI=body mass index; CHF=chronic heart failure; eGFR=estimated glomerular filtration rate

Safety endpoints in FAIR-HF Patients with events (Incidence per 100-patient years at risk) FCM (N=305) Placebo (N=154) p Death 5 (3.4) 4 (5.5) 0.47 CV death 4 (2.7) 0.31 Death due to worsening HF 0 (0.0) 3 (4.1) – First hospitalisation 25 (17.7) 17 (24.8) 0.30 Hospitalisation for any CV reason 15 (10.4) 14 (20.0) 0.08 First hospitalisation for worsening HF 6 (4.1) 7 (9.7) 0.11 Any hospitalisation or death 30 (21.2) 19 (27.7) 0.38 Hospitalisation for any CV reason or death 20 (13.9) 16 (22.9) 0.14 First hospitalisation for worsening HF or death 11 (7.5) 10 (13.9) 0.15 CV=cardiovascular; HF=heart failure Anker SD, et al. N Engl J Med 2009;361:2436–48.

Intravenous iron in CHF FAIR-HF Patients with anemia Patients without anemia % Filippatos, Farmakis , Parissis , et al. Eur J Heart Fail 2013

FAIR-HF results: impact of FCM on renal function Treatment effect (mL/min/1.73m2)*: 2.8 ± 1.5 3.0 ± 1.5 4.0 ± 1.7 *LSM mean ± SE; LSM=least squared mean Ponikowski P, et al. Heart Failure Association Congress 2010; abstract 114 and late-breaking trial oral presentation.

FAIR-HF results: primary endpoints by baseline eGFR NYHA functional class Patient Global Assessment <60 mL/min/1.73 m2 ≥60 mL/min/1.73 m2 PInteraction 0.17 0.18 0.42 PInteraction 0.11 0.85 0.46 Ponikowski P, et al. Heart Failure Association Congress 2010; abstract 114 and late-breaking trial oral presentation.

CONFIRM-HF Change in 6-min walk test (Primary endpoint) Week 24 LSM change in 6MWT distance from baseline (m) FCM (N=150) Placebo (N=151) 30 20 10 -10 -20 -30 Ponikowski P et al Eur Heart J 2014

CONFIRM-HF First hospitalization due to worsening HF 10 20 30 Hospitalization rate (per 100 subjects) 180 270 360 90 Time (days) Placebo FCM Log–rank test P=0.009 Ponikowski P et al Eur Heart J 2014

Effects of ferric carboxymaltose on hospitalisations and mortality rates in iron‐deficient heart failure patients: an individual patient data meta‐analysis Rate ratios for cardiovascular hospitalisations and cardiovascular mortality for the individual randomised controlled trials included in this meta‐analysis. CI, confidence interval; FCM, ferric carboxymaltose. IF THIS IMAGE HAS BEEN PROVIDED BY OR IS OWNED BY A THIRD PARTY, AS INDICATED IN THE CAPTION LINE, THEN FURTHER PERMISSION MAY BE NEEDED BEFORE ANY FURTHER USE. PLEASE CONTACT WILEY'S PERMISSIONS DEPARTMENT ON PERMISSIONS@WILEY.COM OR USE THE RIGHTSLINK SERVICE BY CLICKING ON THE 'REQUEST PERMISSIONS' LINK ACCOMPANYING THIS ARTICLE. WILEY OR AUTHOR OWNED IMAGES MAY BE USED FOR NON-COMMERCIAL PURPOSES, SUBJECT TO PROPER CITATION OF THE ARTICLE, AUTHOR, AND PUBLISHER. European Journal of Heart Failure 24 APR 2017 DOI: 10.1002/ejhf.823

Iron therapy in HF Unanswered questions Large-scale trials? Prognosis? Long-term safety? Who really benefits? Hb target in anemia? Hb restoration rate?

ID in HF: Ongoing trials

THANK YOU FOR ATTENDING